DK141250B - Analogous process for the preparation of 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-ones. - Google Patents

Description

(11) SUBMITTED66EL3ES8CRIPTION 1M250 DENMARK (51) Int. Cl.3 C 07 O 487/04 § (21) Application No. 5 & l / l6 (22) Indict on 13 · Feb. 1375 (23) Runs «1 3 · f eb. 1 976 (44) The application submitted and the petition 'published on 11 Feb. IgQø

Dl THE RECTORATE FOR

PATENT AND TRADE MARKET (30) Priority requested from 15 Feb 1975 * 6509/75 qb Nov 4 1975, 45800/75, gb (71) ROUSSEL-UCLAF S.A., 35, Boulevard des Invalides, 75007 Paris # ER.

(72) Inventor: John Bodenham Taylor, 3 Suffolk Place, Down Ampney, Nr. Cirencester, Gloucestershire, GB: Derek Ralph Harrison, 3, Goddard Avenue, Swindon, Wiltshire, GB.

(74) Plenipotentiary in the proceedings *

Patent law firm Magnus Jensens Eftf.

(64) Analogous process for the preparation of 1,2-dihydro-6-phenyl-1H, 4H-imidazo (1,2-a) (1,4) benzodiazepin-1-ones.

The invention relates to an analogous method for the preparation of novel pharmaceutically active 1,2-dihydro-6-phenyl-1H, 4H-imoazo [T, 2- & 7 / Itffi] enzoaziazvin-1-one which can be used in the human or veterinary medicine. , and which has the general formula I or salts thereof specified in the preamble of the claim.

Where R 1 represents a halogen atom, this may be a fluorine, chlorine or bromine atom, but it is preferably a chlorine atom.

2

Where R represents a halogen atom, this may also be a fluorine, chlorine or bromine atom, but it is preferably a fluorine or chlorine atom. Furthermore, the halogen atom R · is preferably in the o-position.

Which one of the symbols R ^ and I? represents an alkyl group, it may be methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl or pentyl, but preferably represents methyl, ethyl, n-propyl, n-butyl or T41ZSO 2 or text.-butyl.

4 5

Where one of the symbols R and R represents a hydroxyalkyl group, the alkyl moiety may be methyl, ethyl, propyl, butyl or pentyl, but is preferably ethyl.

A C

Where one of the symbols R and R represents an aminoalkyl or alkylaminoalkyl group (which last term includes both monoalkyl and dialkylaminoalkyl), each of the alkyl moieties may conveniently be methyl, ethyl, propyl or butyl, but is preferably methyl or ethyl.

preferably R 1 and / or R 2 represent aminomethyl, aminoethyl, dimethylaminoethyl or diethylaminoethyl, but may also represent aminopropyl, aminobutyl, methylaminomethyl, methylaminoethyl or dimethylaminopropyl.

Hair one of the symbols R 1 and R 2 represents a cycloalkyl group,

it is preferably a cyclohexyl group. i R

R 1 and R may be the same - e.g. each being a methyl group - or different, and when different, one of them is preferably hydrogen.

Within the broad range covered by the general formula Ic, the following smaller groups of substances are preferred: a) the imidazole benzodiazepines of the general formula Ic, wherein

A K

either R and R, which may be the same or different, each represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, a hydroxyethyl group, a dimethyl or diethylaminoethyl group, a phenyl-4, β group or a cyclohexyl group, or R and R together with the nitrogen atom forms a pyrrolidinyl, piperidino, morpholino, thio-morpholino, piperazin-1-yl, 4-alkylpiperazin-1-yl, 4-hydroxyethyl-piperazin-1-yl, 4-phenylpiperazine-1 -yl or 4- (1'-phenyl-5, -imidazolyl-4'-one) -piperidin-1-yl group.

b) the imidazole benzodiazepines of the general formula Ic, wherein 1 2 R represents a chlorine atom or a nitro group, R represents a hydrogen atom, a chlorine atom or a fluorine atom, and wherein either R and R, which may be the same or different, each represents a hydrogen atom, a straight chain alkyl group of 1 to 5 carbon atoms, a hydroxyethyl group, a phenyl group or a cyclohexyl group, or wherein R and R together with the nitrogen atom form a piperidino, morpholino, piperazine-1-yl, 4-alkylpiperazine -l-yl or 4-hydroxyethylpiperazin-1-yl group; c) the imidazole benzodiazepines of the general formula Ic, wherein an ehlor atom or a nitro group represents H 2 represents a hydro gene, chlorine or fluorine atom. and wherein either R * represents a hydrogen 3

1412SO

atom and Ir represents methyl, ethyl, propyl or butyl or where λ ς R and R together with the nitrogen atom form a piperazin-1-yl-, 4-ethyl-piperazin-1-yl-, 4-ethylpiperazin-1-yl -, 4-propylpiperazine-1-yl or 4-hydroxyethylpiperazin-1-yl group, d) the imidazole benzodiazepines of the general formula Io, wherein R 1 represents an ehloro atom or a nitro group, represents a hydrogen, chloro or fluoro atom, and and together with the nitrogen atom forms a 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl or 4-propylpiperazin-1-yl group, e) the imidazole benzodiazepines of the general formula Io, wherein R · represents a hydrogen atom, a e represents a hydrogen atom, an e-chlorine atom or a fluorine atom, and B * and c R together with the nitrogen atom form a 4-dimethylphosphinylB-thylpiperazin-1-yl group, and f) the imidazole benzodiazepines of the general formula wherein R1 represents a hydrogen atom, an ehloro atom or a nitro group, R2 represents a hydrogen atom or an ehloro atom, and E * and E * together with the nitrogen atom forms a d-dimethylphosphinyllaethylpiperazin-1-yl group.

The imidazole benzodiazepines lo may be in the form of acid addition salts, and the dies may be salts with mineral acids or organic acids. Typical mineral acids are hydrochloric acid, hydrobromic acid, hydrogen iodide acid, nitric acid, sulfuric acid and phosphoric acid, while typical organic acids are acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, oxalic acid, glycolic acid, aspartic acid, aspartic acid, aspartic acid. . Preferred acid addition salts are typically the rates and alkane sulfates, and are preferably preferred with the sulfates.

Here are further preferred groups of compounds of formula Ic in the form of acid addition salts. Eisse is as follows: g) acid addition salts of the imidazole benzodiazepines of the general formula Io, wherein E1 represents a hydrogen atom, an ehloro atom or a nitro group, R 2 represents a hydrogen atom, an ehloro atom or a fluorine atom, and E And (h) tartraterae and alkane sulfonates, in particular the methanesulfonates, of the imidazole benzodiazepines of the general formula Io, wherein R1 represents an ehloro atom or a nitro group, E2 represents a hydroxyl. 5 genome or a chlorine atom, and R and R together with the nitrogen atom form a 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group.

Particularly preferred imidazole benzodiazepines of the general formula Ic and their salts are: 8-chloro-1,2-dihydro-2- (H-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo / T, 2α, α, 47benzodiazepin-1-one (Example 7A), 8-chloro-1,2-dihydro-2- (N-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H -imidazo [1,2-a7 / T, 4-benzodiazepin-1-one tartrate (eca.7B), 8-chloro-1,2-dihydro-2- (R-hydroxyethylpiperazin-1-yl) - methylene-phenyl-1H, 4H-imidazo / T, 2-a7 / T, 4 / benzodiazepin-1-one (Ex. 9) »8-Chloro-1,2-dihydro-2- (N-methylpiperazine -1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [2,2-a] benzodiazepin-1-one (ex.Il), 8-cblo r-1,2 -Dihydro-2 - (R-methyl-1-piperazin-1-yl) -methylene-6 - (o-chlorophenyl) -IH, 4H-imidazo [1, 2-a // 1 * 4 / benzodiazepine -1-one-tar-trate (Example 11B), 8-nitro-1,2-dihydro-2- (IT-methylpiperazin-1-yl) methylene-6-phenyl-1H, 4H- imidazo [1,2-a // 1,4 / benzodiazepin-1-one (ex. 12), 8-chloro-1,2-dihydro-2- (n-butylamino) -methylene-6-phenyl -1H, 4H-imidazo [1,2-a // I, 47benzodiazepin-1-one (Ex. 14), 8-Chlo rl, 2-dihydro-2- (R-methylpiperazin-1-yl) -methylene-6 - (o-fluorophenyl) -1H, 4H-imidazo [1,2-a7], 4 / benzodiazepine l-one (ex. 22), 8-Chloro-1,2-dihydro-2- (n-propylamino) methylene-6-phenyl-1H, 4H-imidazolo [2,2-a] 7 / 1,4-benzodiazepine 1-one (Ex. 27), 8-nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo / 1, 2-§7β, 4β-benzodiazepin-1-one (ex. 28) 8-nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -methylene- * 6- (o -chlorophenyl) -1H, 4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one methanesulfonate (ex. 48), 8-nitro-1,2-dihydro-2- (H- methylpiperazin-1-yl) -methylene-6 - (or fluorophenyl) -1H, 4H-imidazo [1,2-a] 1,4-benz or iazepin-1-one (Ex. 29), 8-chloro-l, 2-dihydro-2- (H-ethylpiperazine-l-yl) methylene-6 - phenyl-lH, 4H-imidazo / l, 2-a // I, 4 / benzodiazepine-L- on (ex. 50), 8-chloro-1,2-dihydro-2- (H-propylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-a] l , 4 / benzodiazepin-1-one, (Example 31), 8-chloro-1,2-dihydro-2- (H-ethylpiperazin-1-yl) methylene-6-- (o-chlorophenyl) -IH, 4H-imide azo / 1,2-a // 1,4, benzodiazepine-1-one. (Ex. 36), 8-Chloro-1,2-dihydro-2- (H-ethylpiperazin-1-yl) methylene-6- (o-fluorophenyl) -1H, 4H-imidazo [1,2-a // i, 4 / Benzodiazepin-1-one (Ex. 37), 8-nitro-1,2-dihydro-2- (N-ethylpiperazin-1-yl) methylene-6- (o-chlorophenyl) - 1H, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one (ex. 38), 8-nitro-1,2-dihydro-2- (JT-ethylpiperazine-1-one) yl) -ethylene-6- (o-fluorophenyl) -1H, 4H-imidazo [1,2-a], 4-benzodiazepin-1-one, (eke # 39), 8-chloro-1 , 2-dihydro * -2- (ethylamino) -ethylene-6-phenyl-1H, 4H-imidazo [1,2-a7 / 1,4]; 3-enzodiazepin-1-one. (Example 40), 8-Chloro-1,2-dihydro-2- (ϊΓ-dimethylphosphinylmethylpiperazin-1-yl) methylene-6-phenyl-1Hr4H-imidazo / If 2-a 1, 4 / Benzodiazepin-1-one (Example 41), 8-Chloro-1,2-dihydro-2- (1-dimethylphoephinylmethylpiperazin-1-yl) methylene-6 - (o -ohloropheny 1) -IH, 4H-imid az ο / ϊ, 2-a // ί, 4 / benz ο-diazepin-l-one. (Ex. 45) 1,2 1,2-dihydro-2- (JSr-dimethylphosphinylmethylpiperazia-1-yl) -; -methylene-6-phenyl-1H, 4H-imidazo [1], [beta] -benzodiazepin-1-one (ex, 46), 8-nitro-1,2-dihydro-2- (t -l-yl) -methylene ~ 6- (o-chlorophenyl) -1H, 4H-iHidazo [1, 2-a7 / 1, 4 / benzo-diazepin-1-one (Ex. 47) ·

Of these particularly preferred compounds, 9-nitro-1 # 2-dihydro-2- (H-methylpiperazin-1-yl) methylene-6- (o-chlorophenyl) -1H, 4H-imidazo / 1,2-a7 / 1,4 / benzod iazepine-1-on-ethanesulfonate showed a remarkable remarkable pharmacological activity.

The imidazole benzodiazepines of the general formula Io can be conveniently prepared by a process starting from the corresponding compounds which are unsubstituted at the 2-position, and these can again be prepared from the corresponding 2-alkoxycarbonyl or 2-carboxymethylaminobenzodiazepines.

The process according to the invention is characterized by the characterizing part of the collar.

The reaction with the ketal VI is conveniently carried out in an anhydrous organic solvent, for example, an arene such as benzene, and in the presence of a base, preferably a nitrogen-containing base such as an amine, e.g. triethylamine.

The reaction with the amine VIII is conveniently carried out in an anhydrous organic solvent, e.g. an arene such as toluene and at a high temperature which is preferably the boiling point temperature of the reaction mixture. It will be understood that when one wishes to form a compound Ic where B and R are both hydrogen, the compound VIII used for the transamination will be ammonia itself.

6 T41250

The imidazole benzodiazepine V used as starting material can be prepared from a compound of formula II

n (ii> 1 2

wherein R and R have the same meaning as above, by reacting them with a compound of formula III

0 C - CH «t 1 * R-0 ΙΊΗρ

wherein R represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms to form a compound of formula IV

Wherein R, R and R have the same meaning as above, which is reacted with a dehydrating agent to give the desired compound of formula V .

7 141260

The reaction of Compound II with Compound III is advantageously carried out in an organic solvent, preferably an alcohol such as ethanol and at a hay in temperature which is conveniently the boiling temperature of the reaction mixture.

The dehydrating agent which is reacted with the acid 17 is conveniently a carbodiimide such as dicyolohexyloarbodiimide and the reaction is advantageously carried out in a chlorinated alkane such as methylene chloride. The ro-light of the ester 17 is conveniently carried out in a high boiling solvent such as an arene, e.g. toluene.

To prepare acid addition salts of the compounds of the general formula Ic, a suitable compound Ia or Ic is reacted in practically stoichiometric amounts with a suitable inorganic or organic acid to form the desired acid addition salts.

The conversion to salt is conveniently carried out in an organic solvent or a mixture of organic solvents such as one or more alkanols, e.g. methanol or ethanol, and / or one or more alkyl halides, e.g. methylene chloride.

Imidazole benzodiazepine-1-ones of formula Io and their acid addition salts have very interesting pharmacological properties.

In particular, they have remarkable sedative, hypnotic, anxiety-reducing, sedative, anticonvulsant, and myorelaxative properties that may make the compounds of formula IO and their pharmaceutically acceptable acid addition salts interesting as drugs for the treatment of arousal or irritation states or by aggression, insomnia, certain insomnia, in certain disorders of character and behavior, and in certain spasms and muscular contractions.

The following is well-known in the art:

No. 2,237,592 discloses 4H-imidazole, 2-a7 </ T, 47benzodiazepines which are substituted: - at the 1-position with a hydrogen atom or methyl, ethyl or propyl, - at the 2-position with a hydrogen atom or alkyl of 1-3 carbon atoms, at the 6-position with various substituents such as pyridyl, 2-pyrimidyl, furyl, pyrryl, thienyl or phenyl optionally substituted.

The compounds of the present invention are derivatives of 4H-imidazo ^ T, 2-8 ^^, Tbenzodiazepines, U1250 8 which are substituted: - at the 1-position with a ketone group, - at the 2-position with a group of the formula

H

»= C-ir-R4 to R5 - at the 6-position with an optionally substituted phenyl group ·

Thus, the compounds prepared by the process according to the invention differ from the prior art compounds in particular in that they have a ketone group at the 1-position instead of a hydrogen atom or an alkyl group, and also by having an aminomethylene group at the 2-position. instead of a hydrogen atom or an alkyl group having 1-3 carbon atoms.

In addition, the compounds prepared by the process of the invention do not have a heterocyclic group substituent at the 6-position.

No substance according to the aforementioned prior art is known to be commercially available.

The compounds disclosed in German Publication No. 2,321,705 are derivatives of 4H-imidazo / 1,2 / 4,4-benzodiazepines which are substituted: - in the 1-position with a hydrogen atom, a methyl group or a hydroxy group, - at the 2-position with a hydrogen atom or a halogen atom, - at the 4-position with a hydrogen atom, a hydroxy group or a low molecular weight alkyl group.

The compounds prepared by the process of the invention are derivatives of 4H-imidazo / T, 2-7,7 T, 7benzodiazepines which are substituted: - in the 1-position with a ketone group, - in the 2-position with an aminomethylene group, - in 4 position with a hydrogen atom.

Thus, the compounds prepared by the process according to the invention also differ from those of the prior art in that they do not have the same type of substituents in the 1- and 2-positions and, where appropriate, in the 4-position.

Also no known product according to this technique is known to be commercially available.

In view of the fact that no product according to the above-mentioned prior art is commercially available, the activity of the compounds prepared by the process according to the invention has been compared with the activity of a widely commercialized substance which presents an activity in analogy with the activity of the process according to the method of compounds of the invention *, namely chlordiazepoxide, known under the registered trade mark librium *

The results obtained are shown in Table 3 in the experimental section below.

The results obtained show, for most experiments and for a large majority of the compounds, that the compounds prepared by the process of the invention are far more active than the comparative product.

The soothing effect of the compounds prepared by the process according to the invention is particularly evident, e.g. In the A.A.M. test, all of the compounds prepared by the process of the invention exhibit an activity greater than the activity of chlorodiazepoxide, which is a very well-known sedative. Furthermore, as is evident from the P.H.M. test, some of the products produced by the process of the invention present very significant hypnotic properties.

However, before any of the compounds of formula Io and their pharmaceutically acceptable acid addition salts can be used in the medicine, they should preferably be formulated into pharmaceutical products by association with appropriate pharmaceutical carriers.

The term "pharmaceutical" is used here to exclude any possibility that the nature of the carrier, assessed in connection with the mode of administration, may be harmful rather than beneficial. The choice of an appropriate formulation as well as an appropriate carrier is within the competence of professionals.

The compounds of formula Io can be used to prepare pharmaceutical products containing one or more imidazole-benzodiazepine-1-ones Ic or pharmaceutically acceptable acid addition salts thereof in association with a suitable pharmaceutical carrier.

T 2 2-Carboxymethylamino-7-R -5- (R-phenyl) -3H-1,4-benzodiaze pinene IV and the corresponding 2-alkoxycarbonylmethylamino-7-R 5 -5- (E2-phenyl) -3H 1,4-benzodiazepines IV, wherein the alkyl group R is different from ethyl, are novel compounds.

The following examples illustrate the method of the invention.

1 * 1250 10

Example 1.

8-chloro-l. 2-Dihydro-2- (d imethylamino) -ethylene-6-phenyl-1S.45 - imidazo [1, 2-a7 / 1,4, benzodiazepin-1-one la.

lane A: 2-carboxymethylamino-7-ohloro-5-phenyl-5H-1,4-benzodiazepine IJ.

7- Chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione II (3 * 5 g) * glycine III (5 * 5 g) and sodium carbonate (5 *) 5 g) are suspended in ethanol (100 ml) and water (30 ml) and stirred and refluxed for 1 hour. The suspension is then poured into water to give a clear solution and it is acidified to a pH of 4 with 2N HCl and extracted with OHOl. Some solid precipitates from the extracts and is filtered off.

The organic layer is dried over MgSO 4 and evaporated to give a gum which crystallizes by rubbing off with methanol. This solid and the filtered solid above are crystallized from a large amount of ethanol to give 2-carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, 3.1 g (77 $). Mp. 215-220 ° C.

Step B: 8-Chloro-1,2-dihydro-6-phenyl-ΙΗ, 4H-imidazo [1,2-a7], 4 [beta] -diazepin-1-one 7.

2-Carboxymethylamino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (2.5 g) is suspended in dry CH 2 Cl 2 (120 ml) and stirred, and dicyelohexylcarbodiimide (2.1 g) is added. The suspension is stirred at room temperature for 3 hours and then filtered and the filtrate is evaporated to give 8-chloro-1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-a7 </i> 47benzodiazepine -l-on V in the form of a colorless oil, which is used immediately in the next step.

Step 0: 8-Chloro-1. 2-Dihydro-2 - (d ime th.vlamino) -me thylene-6-phenyl-1H, 4H-imidazo [1, 2-a7 / 4] 4.Aepzodiaaepin-1-one la.

8- Chloro-1,2-dihydro-6-phenyl 1-1H, 4H-imide az o / It 2-a // 1,4 / benz o -diazepin-1-one Y from step B above is dissolved in dry benzene, and dimethylformamide diethyl acetal YI (1.5 g) and triethylamine (1 ml) are added. The solution is stirred at room temperature for 1 hour 30 minutes and then evaporated to give a brownish yellow residue. Recrystallization of a mixture of ethyl acetate and methanol gives pale yellow rods of 8-chloro-1,2-dihydro-2- (dimethylamino) methylene-6-phenyl-1H, 4H-imidazo / I, 2-a7 / 1,4 / benzodiazepine-1-one la, 2.7 g ($ 97). Mp. 264-265 ° C.

141250 11

Analysis: C20H17C11T40 = 364.9 Calculated: C # 65.85 H # 4.66 15.37 Cl £ 9.74 Found: 65.87 4.67 15.37 9.79 IR Spectrum (KBr Disc): 0 = 0 at 1690 cm * 1, C = N at 1621 cm -1.

Examples 2-6.

Using a similar method as in Example 1, the following compounds 17, 7 and Ia are prepared:

Example Compounds 2 17 j 2 -carboxymethylamino-7-nitro-5-phenyl-3H-1,4-benzodiazepine.

7: 8-Nitro-1,2-dihydro-6-pbenyl-1H, 4H-imia azo / 1,2-a / i, 4 / benzodiazepin-1-one.

Ia: 8-nitro -1,2-dihydro-2- (dimethylamino) -methylene-6-phenyl-1H, 4H-imidaxo / 1,2-a // 1,4 / benzod iazepin-l-one.

3 17: 2-carboxymethylamino-7-chloro-5-o-chlorophenyl-3S-1,4-benzodiazepine.

7: 8-Chloro-1,2-dihydro-6-o-chlorophenyl-1H, 4H-imidazo / 1,2-a7 / 1,4 / benzodiazepin-1-one ·

Ia: 8-Ehloro-1,2-dihydro-2- (dimethylamino) methylene-6-o-chlorophenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepine pin-l-one.

4 17: 2-oreboxymethylamino-7-nitro-5-o-chlorophenyl-3H- -1,4-benzodiazepine.

7: 8-Nitro-1,2-dihydro-6-o-chlorophenyl-ΙΗ, 4H-imidazole [2,2-a] [1,4] benzodiazepin-1-one ·

Ia: 8-Nitro-1,2-dihydro-2- (dimethylamino) -methylene-6-o-chlorophenyl-1H, 4H-imidazo [1,2] -a // 1,4-benz or the like - pin-l-one.

IV: 2-Carboxymethylamino-7-chloro-5-o-fluorophenyl-3H- -1,4-benzodiazepine.

V: 8-Chloro-1,2-dihydro-6-o-fluorophenyl-1H, 4H-imidazo / 1,2-a // 1,4-benzodiazepin-1-one.

Ia: 8-Chloro-1,2-dihydro-2- (dimethylamino) -methylene-6--o-fluorophenyl-1H, 4H-imidazo [1,2-a], 4 / benzodiazepine-pin-1 -on.

Example Compounds 12 IV: 2-Carboxymethylamino-7-nitro-5-o-fluorophenyl-3H- -1,4-benzodiazepine.

7: 8-Nitro-1,2-dihydro-6-o-fluorophenyl-1H, 4H-imidazo [2,2-a] 1,4-benzodlazepin-1-one, 1a: 8-nitro-1,2 -Dihydro-2- (a ime thylamino) -me thylen-6 - -o-fluorophenyl-1H, 4H-imidazole, 2-a7 / 1, 4 / benzod ia-zepin-1-one.

In each case, the compound III is glycine, the compound VI is dimethylformamidethyl acetal, the compound V is used without further purification, and the crystallization solvent for the compound 1a is methanol. The data of these compounds (with the exception of compounds 7) are listed in Table 1 below.

Table 1.

'* C

EXAMPLE 17 17a, -M R is dimethylamino example Yield mp ° C Crystalline R R yield m.p. ° C $ s of ions solution _________ agent _ _ _ _ 2 66 154-5 MeOH ΙΓ02 H 43 227-8 3 75 136-9 MeOH-EtgO Cl o-Cl 53 288-90 4 83 158-61 EtgO N02 o-Cl 78 253-5 5 69 rubber - Cl oF 63 257-60 $ 44 - Et20 M> 2 oF 80 228-31

Example 7

8-chloro-l. 2-dihydro-2- (1-methyl-piperazin-1-yl) -methyl-6-phenyl-1H, 4H-imidazo [1,2-a] [1,4] benzodiazepine 1-on Ic and its tartrate, A) 8-Chloro-1,2-dihydro-2- (dimethylamino) -methylene-6-phenyl-1H, 4H-imidazo / 1,2-a / 71 , 4 / benzodiazepine-1-one 1a (prepared as in step C of Example 1) (2.3 g) and R-methylpiperazine (4.0 g) are stirred under reflux in dry toluene (50 ml) for 24 hours. On cooling, crystals stand out, which are filtered off. Evaporation of the solvent gives a pale yellow solid and this is treated with methanol and filtered. The two groups of solids are combined and recrystallized from a mixture of methanol and ethyl acetate to give 8-chloro-1,2-dihydro-2- (R-methylpiperazin-1-yl) methylene-6-phenyl 1H, 4H-imidazo / 1,2-a // I, 4y7benzodiazepine-1-one Ic, 2.3 g (87 $). Mp. 255-256 ° C.

141250 13

Analysis: C23H2201Ift; 0 = 419.9 calculated: (# 65.80 H # 5.24 Η * 16.69 02 # 8, -46 found: 65.64 5.27 16.63 8.56 IH spectrum (KBr dial): C = 0 at 1705 cm -1, C = N at 1635 and 1 B) The tartrate of 8-chloro-1,2-dihydro-2- (1-methylpiperazin-1-yl) methylene 6-Phenyl-1H, 4H-imidazo [1,2-a7] Ir4 / benzodiazepin-1-one Ic is prepared by adding a stoichiometric amount in methanol of tartaric acid to 8-chloro-1,2-dihydro-2- (H -aethylpiperazin-1-yl) -aeethylene-6-phenyl-1H, 4H-imidazole, 2-% 7 / L, 4 / benzodiazepin-1-one.

The crude salt formed was recrystallized from methanol to give the desired product. Mp. 146-150 ° C.

Analysis: CgyEE øClClClijOO = 570.1 calculated: G $ 56.89 H% 4.92 BT # 11.29 Cl # 6.23 found: 56.44 4.93 11.79 5.93 IR spectrum (EBr dial): OH at 3400 about "1 and 2500 about" 1, 0 = 0 at 1730 about "1 and 1690 cm" 1, C = N at 1630 cm "1.

Example 8-44 / SOB In these examples, unless otherwise indicated, a process analogous to that used in the preparation of 8-chloro-1,2-dihydro-2- (N-methylpiperazine-1 yl) -methylene-6-phenyl-ΙΗ, 4H-imidazo / L, 2-a // L, 4 / benzodiazepin-1-one Ic in Example 7 to prepare the following compounds I:

Example Compound I

8 8-Chloro-1,2-dihydro-2- (morpholino) -methylene-6-phenyl-1H, 4H-imidazo / L, 2-a / 1,4, benzodiazepin-1-one.

9 8-Chloro-1,2-dihydro-2- (1-hydroxyethylpiperazin-1-yl) -methylene-6-phenyl-1 H, 4B-1-imid as o / l, 2-a / l, 4 / benz or iazepin-1-one.

8-Chloro-1,2-dihydro-2- (N-phenylpiperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] L, 4 / benzodiazepine -1-one.

11 8-Chloro-1,2-dihydro-2- (1-methylpiperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] l, 4 / benzo-diazepin-l-one.

Example 8 Compound I-8-Chloro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -methyl-6- (o-chlorophenyl) -1H, 4H-imide az o / l, 2-a // 1,4-benzo-diazepine-1-one tartrate.

Method: Analogous to Example 8B.

12 8-Nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imidazo [1,2-a] 1,4-benzodiazepine --1-one.

8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methylene-6--phenyl-1H, 4H-imidazole / 1,2-af / 1,4 / benzodiazepine-1 -one »8-Chloro-1,2-dihydro-2- (n-butylamino) -methylene-6-phenyl-1H, 4H-imidazo / L, 2-alpha / 1,4-benzodiazepine-1 8-Chloro-1,2-dihydro-2- (amino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] [4] benzodiazepine-1 one.

Method: 8-Chloro-1,2-dihydro-2- (dimethylamino) -methyl-6-phenyl-1H, 4H-imidazo </i>, 2-a // I, 4 / benzodiazepine -1-one la (2.1 g) is suspended in dry methanol (100 ml). The suspension is stirred, cooled in a bath of dry ice and acetone, and ammonia gas VIII is bubbled through for 15 minutes. The suspension is then warmed to room temperature, stirred for a further 2 days and the solvent is evaporated. The solid residue is recrystallized from a mixture of methanol and ethyl acetate to give 8-chloro-1,2-dihydro-2- (amino) -methylene-6-phenyl-ΙΗ, 4H-imidazo / I, 2- a // I, 4 / benzodiazepine-1-on Ic, 1.9 g ($ 98), m.p. 265-267 ° C.

16 8-Chloro-1,2-dihydro-2- (piperidino) -methylene-6-phenyl-1,4-4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one.

17 8-Chloro-1,2-dihydro-2- (thiomorpholino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one.

18 8-Chloro-1,2-dihydro-2- (diethylaminoethylamino) methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one.

19 8-Chloro-1,2-dihydro-2- (N-methyl-1- (N-dimethylamino) -ethyl-amino) -methylene-6-phenyl-1H, 4H-imidazo / 1,2-a // 1,4, benzo-diazepin-1-one.

8-Chloro-1,2-dihydro-2- (methylamino) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one.

21 8-Chloro-1,2-dihydro-2- (cyclohexylamino) methylene-6-phe-new 1-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepin-1-one.

Example _ Compound I

8-Chloro-1,2-dihydro-2- (H-methylpiperazin-1-yl) ethylene-6- (or luorphenyl) -1H, 4H-imidazo / l, 2-% 7 / l , 4 / benzod iazepin-l-on.

23 8-ehloro-1,2-dihydro-2- (4- (1 * -phenyl-5 * -imidazolyl-4'-one) -piperidin-1-yl) -methylene-6-phenyl] 1H, 4H-iazazo / 1,2-a // 1,4-benzo (3 iazepin-1-one, 24 8-chloro-1,2-dihydro-2- (phenylamino) methylene-6-phenyl) --lH, 4H-imidazo / l, 2-a // l, 4 / benzodiazepine-l-one.

Methods 8-Chloro-2- (1 * - (diethylamino) ethylidene) -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-ayr / 1,2,4-benzodene lock - pin-l-on 1b (Example 7) (2.3 g) and H-1-ethylpiperazine VIII (15 ml) stirred at 120 ° C under nitrogen atmosphere for 9 hours · Pour cooled solution into Tooth which is added to JfaCl to complete The precipitate and the brown precipitate are filtered off, dissolved in CHCl3, washed with yand, dried ores MgSO4 and evaporated, then a dark red oil is stirred. hTorred to obtain 8-chloro-2- (1 * - (IT-methylpiperazin-1-yl) -ethylidene) -1,2-dihydro-6-phenyl-1H, 4H-imidazo [1,2-a7] / l, 4 / benzodia * epin-l-on Id, 1.0 g (3856). Mp. 193-195 ° C.

8-Chloro-1,2-dihydro-2- (tert, -butylamino) -oethylene-6-phenyl-1H, 4H-imidazo [1,2-a] l, 47benzodiazepin-1-one.

26 8-Chloro-1,2-dihydro-2- (hydroxyethylamino) -methylene-6-phenyl-1H, 4H-imidazole [2,2-a] 1,4-benzodiazepin-1-one.

27 8-Chloro-1,2-dihydro-2- (n-propylamino) -methylene-6-phe-new 1 -IH, 4H-imide az o / 1, 2-% 7 / 1,4 / benzod 8-nitro-1,2-dihydro-2- (1H-methylpiperazin-1-yl) -phyllethylene-6- (o-chlorophenyl) -1H, 4H-imidazole , 2sJ / lt 4 / benzo-diazepin-1-one.

2,9-Nitro-1,2-dihydro-2- (ff-methylpiperazin-1-yl) -methylene-6- (or luorphenyl) -1H, 4H-imidazo [1,2-a] I-4 / benzo-diazepin-l-one.

8-Chloro-1,2-dihydro-2- (N-ethylpiperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepine --1-one.

141250 16

Example Compound I

30B 8-Chloro-1,2-dihydro-2- (H-ethylpiperazin-1-yl) -methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepine --1-on-tartrate.

Method: Analogous to Example 8B.

31 8-Chloro-1,2-dihydro-2- (N-propylpiperazin-1-yl) methylene-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4 / benzod iazepine - 1-ounce.

32 8-chloro-1,2-dihydro-2 - (E- (n-butyl) -piperazin-ly 1) -methylene-6-phenyl-1-1H, 4H-imidazo / I, 2-7 / A I-4 / benzodiazepine-zepin-l-one.

33 8-Chloro-1,2-dihydro-2- (N- (isopropyl) -piperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imide azo / ϊ, 2-a // 1 , 4 / benzod iaze -pin-l-on.

Method: 8-chloro-1,2-dihydro-2- (piperazin-1-yl) -methyl-6-phenyl-1H, 4H-imidazo [1,2-a] 1,4-benzodiazepine -1-one (the compound of Example 13 prepared as in Example 8) (1.5 g), isopropyl iodide (2.5 g) and sodium carbonate (30 g) is stirred at 80 ° C in aeetonitrile (25 ml ) and methylene chloride (5 ml) for 18 hours. The cooled solution is poured into water and extracted with chloroform. The extracts are washed with water, dried over MgSO 4 and evaporated to give a pale yellow solid. Recrystallization of this ethyl acetate solid gives 8-chloro-1,2-dihydro-2- (H- (isopropyl) -piperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imidazo / 1,2 -a // l, 4 / benzodiaze -pin-l-on Ic, 1.2 g (73 $), m.p. 146-148 ° C.

34 8-Chloro-1,2-dihydro-2- (H-allylpiperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imidazo [1,2-a] [1,4] benzod iaze pin-l-on. Method: Analogous to Example 33.

8-Chloro-1,2-dihydro-2- (E-cyclopropylmethylpiperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imide azo / 1,2-aryl, 4,4-benzo diazepin-l-one.

Method: Analogous to Example 33 »36 8-Chloro-1,2-dihydro-2 - (H-ethylpiperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo / 1 2-a // 1,4-benzodia-zepin-1-one.

37 8-Chloro-1,2-dihydro-2- (E-ethylpiperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H, 4H-imidazo [1,2-a] l, 4 / benzod iaze -pin-l-on.

Example __ Front page I-17 8-nitro -1,2-dihydro-2- (BT-tby Ipipe ras in-ly 1) -methyl-6- (o-chlorophenyl) -1Ht4H- imidazo / LT2-A7 / l, 4 / benzodiazepine-pin-l-one.

39 8-Nitro-1,2-dihydro-2- (E-ethylpiperazin-1-yl) -methylene-6- (o-fluorophenyl) -1H, 4H-imidazoyl, 2-% 7 ^ 1,47benzodia -zepin-l-one.

4Q 8-Chloro-1,2-dihydro-2- (ethylamino) -methylene-6-phenyl--1H, 4H-imidazo [1,2-b] benzodiazepin-1-one.

41 8-Chloro-1,2-dihydro-2- (E-dimethylphosphinylaethylpiperazin-1-yl) -methylene -6-phenyl 1-1H, 4H-imi d az o / L, 2 - a // l, Aj henzodiazepine-l-on.

Method: 8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -methyl-6-phenyl-1H, 4H-imidazole, 2-a7 / 1,4-benzodeless pin -1-one. (The compound of Example 13. obtained as in Example 8) (2.5 g), chloromethyl dimethylphosphine oxide (1.0 g) and sodium carbonate (5.0 g) is stirred under reflux in toluene (80 ml) for 3 days. The cooled suspension is partitioned between chloroform and brim, and the alooroform extract is separated, dried on MgSO4 and evaporated to a pale yellow oil which crystallizes with methanol. The solid (unwanted by-product) is filtered off and the filtrate is evaporated to give a pale orange oil. This oil is dissolved in chloroform and chromatographed on silica gel. Elution with chloroform with methanol (5%) gives a pale yellow solid which upon recrystallization of methylene chloride and ether gives 8-chloro-1,2-dihydro-2- (Ed ime thylphosphinylmethylpiperazine-1-yl) -methylene-6-ph enyl-ΙΗ, 4H-imidazo / l, 2- $ 7 / l, 47 benzodiazepin-1-one Ic (1.25 g) (41 #), emp. 261-262 ° C.

42 8-Chloro-1,2-dihydro-2- (E-propylpiperazin-1-yl) -methylene-6-o-chlorophenyl-1H, 4H-imidazo / 1,2-a7 / 1,4-benzo diazepin-l-one.

4 3 8-Chloro-1,2-dihydro-2- (e thylamino) -methylene-6-o-chloro-phenyl-1H ^ H-imidazo [i] -aT / lj ^ The ^ zo ^ iazepine -pay.

44 8-Chloro-1,2-dihydro-2- (n-propylamino) -methylene-6-o-o-chlorophenyl-1H, 4H-imidazo [1,2-a7 / L, 4 / benzodiazepine-1 -on.

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Example 45 «8-Chloro-1. 2-Dihydro-2 - (ff-d iaethylphos phinylae thypiperazine-1-yl) - -methylp-6- (o-chlorophenyl) -1H.4H-imidago [1,2-a // I.4 / benzoazepin-1-one.

8-Chloro-1,2-dihydro-2- (piperazin-1-yl) -ene thylene-6- (o-chloro-phenyl) -1H, 4H-imidazo [T, 2-a77I, 4] benzodiazepine-1-one Ic (prepared by a method analogous to Example 7) (850 mg), ehloromethyl-dimethylphosphine oxide (1.0 g), sodium iodide (1.0 g) and sodium carbonate (2.0 g) are stirred under reflux in dry toluene (50 ml) for 24 hours. The cooled solution is partitioned between chloroform and water, and the chloroform extract is separated, dried over magnesium sulfate and evaporated to give a gummy solid. This is chromatographed on silio gel eluting with chloroform to give a solid which, by crystallization, mixture of methanol, ethyl acetate and ether gives 8-chloro-1,2-dihydro-2- (N-dimethylphosphinylmethyl-1-yl) methylene-6- (o-ehlorophenyl) -1H, 4H-imidazo / l, 2-a7 / I, 4 / benzodiazepine-1-one with m.p. 231-234 ° C.

I. R. spectrum (KBr disk): 0 = 0 at 1700 about "1, 0 = E at 1630 about" 1

Example 46

1,2-Dihydro-2- (1-dimethylphosphinylmethylpiperazin-1-yl) -ethylene-6-phenyl-1E, 4H-imidazo [1,2-a] 1,47-bupzodiagepin-1-one.

This compound is prepared by a method analogous to that of Example 49 from 1,2-difaydro-2- (piperazin-1-yl) -methylene-6-phenyl-ΙΗ, 4H-imidazo / 1,2-a7 / 1 4 / Benzod iazepin-1-one lo, which is again prepared by a method analogous to that of Example 7-.

It formed 1,2-dihydro-2- (E-dimethylphosphinylmethylpipe-razin-1-yl) methylene-6-phenyl-1H, 4H-imidazole, 2-% 7 ^ 1,4 / lenzodiaze-pin-1 on lo have m.p. 245-247 ° 0th

I, R. spectrum (KBr disk): C = 0 at 1695 about "1, G = N at 1630 about" 1

Example 47.

8-nitro-1. 2-Dihydro-2 - (H-dimethylphosphinylmethylpiperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] l, 47bepzoiciazepn-1-one.

This compound is prepared by a method analogous to that of Example 45 'from 8-nitro-1,2-dihydro-2- (piperazin-1-yl) -methylene-1- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] l, 4 / benzodiazepine-1-one le, which is again prepared by a procedure analogous to that of Example 7.

It formed 8-nitro-1,2-dihydro-2- (M-dimethylphosphinylmethylpiperazin-1-yl) methylene-6- (o-chlorophenyl) -1H, 4H-imidazole [1,2-a7] I, 4 / 7'benzodiazepine-1-on le has m.p. 245-248 ° C.

I.R. Spectrum (KBr disk): 0 = 0 at 1700 cm -1, C = H at 1642 cm -1

Example 48.

8-Nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -1-methylene-6- (o-chloro-phenyl) -1H-45-imidazo [1,2-a7 / 1. 47benzod iazepin-1-one thanesulfonate.

Methanesulfonic acid (1.1 g) is added dropwise to '8-nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) methylene-6- (o-chlorophenyl) -IH, 4H-imidazo / 1, 2-a / 1, 4 / benzodiazepin-1-one (prepared as in Example 28) (4.6 g) in dry methylene chloride (100 ml) and methanol (5 ml).

Slowly dry ether is added until crystals are formed by scraping and the solution is allowed to crystallize, adding further ether to complete crystallization. The pale yellow solid is filtered off, washed with ether and recrystallized from a mixture of methylene chloride and methanol and ether to give 8-nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -me thyme len-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] l, 47benzod ia-zepini-1-one methanesulfonate (5.4 g), m.p. 205-210 ° C. *

Pharmacological activity.

1) Anti-aggression activity in mice (AAM).

Groups of 20 randomly selected male mice (body weight 25-30 g, strain Tuck T.O.) receive oral doses of either carrier alone (10 mg / kg distilled water) or carrier plus test compound.

Thirty minutes after administration, pairs of mice are placed under a reverse 1 liter pyrex beaker on a metal grid. The grid is connected to a Palmer square generator stimulator and the mice 'feet are electrically stimulated by 90 Y pulses for a duration of 5 milliseconds with a frequency of 2 pulses per second. second for a period of 2 minutes.

This procedure induces fighting in the control mice, with fighting being defined as a frontal aggressive attack, usually by biting, of one mouse on the other. The total number of matches in the control group is calculated.

25 141260 EDjjq of a trial tie is the doe that causes a 50 # reduction in the number of matches in a team. mice that received the compound in comparison with the control team1 (R.E. Tedeschi et al. (1959) S. Pharm. Eacptl. Ther. £ 12, 28-34).

The results are shown in Table 3 below.

2) Anti-convulsion effect against maximal mouse electroshock (AEM).

Groups of 10 mice are orally injected with a test compound into a carrier at various dosage levels, with a control group receiving the carrier alone. 30 minutes after administration, each group is subjected to shock via auricular electrodes using an electro-shock device (Ugo Basile EOT for small mammals).

The shocks used have a pulse width of 0.2 milliseconds and a frequency of 100 Hz, and each shock is given for 0.2 seconds at a current of 55 mA.

The number of mice undergoing tonic extension of their hind limbs is noted. The dose that protects 50 # of the mice (TED ^ q) compared to the control group, noter, and the results are shown in Table 3 below.

3) Anticonvulsant effect against pentylenetetrazole in mice (AJM).

Groups of 10 mice are orally injected with the test compound into a carrier at various dose levels, with a control group receiving the carrier alone. 30 minutes after administration, each mouse receives a subcutaneous challenge of 130 mg / kg pentylenetetrazole (pentylenetetrazole is a central nervous system stimulant) and the mice are placed individually in ovarian control boxes. The number of mice showing tonic convulsions within 30 minutes of the pentylenetetrazole injection is noted, and the results for the tonic phase are expressed as a percentage reduction relative to the control levels.

Using an engineered dose-response curve, the doses that protect 50 # of mice (TED ^ q) from tonus are estimated, as shown in Table 3 below.

4) Anticonvulsant effect against strychnine in mice (ASM).

Groups of 10 mice receive the test compound and vehicle orally at various dose levels, with a control group receiving the vehicle alone. Thirty minutes after administration, each mouse received subcutaneously a challenge of 1 mgAg strychnine (strychnine is a central nervous system stimulant) and the mice are then individually placed in observation boxes. The number of mice exhibiting tonic convulsions within 15 minutes of the strychnine injection was noted.

UtZGtt 26 res, and the results for the tonic phase are expressed as a percentage reduction of the control value. In a constructed dose-response curve, the doses protecting 50 $ of the mice (TED ^ q) from the tonus are estimated, as shown in Table 3 below.

5) Potentialization of hexobarbital in mice (PHM).

A group of 10 control mice receive an effective dose of 20, ED2q, of hexobarbital by intraperitoneal route (150 mg / kg) (hexobarbital is a sedative and hypnotic), followed by an oral dose of either a carrier alone or various oral doses of the carrier and test compound. A number of mice exhibiting loss of the erection reflex for 30 seconds at the time 30 minutes after administration are noted and a dose curve response is constructed. One dose of the test compound causing 50 $ of mice in a group to lose the erection reflex is estimated (EE ^ q) and the results are shown in Table 3 below.

6) Potentialization of the ohlor prosthesis in mice (EXM).

Groups of 10 randomly selected CFIP (Carworth Europe) male mice weighing 20-25 g receive the intraperitoneal (12.5 mg / kg) of the ohlorothrothix (the ohlorothothix is a sedative and antipsychotic drug). One dose consistently causes $ 10 of mice to lose their erect reflex 30 minutes after administration. At the same time, the control group of mice received either vehicle alone (distilled water, 10 ml / kg) or a dose of vehicle plus test compound. Each mouse is then individually placed in a small observation chamber and observed for loss of erection reflex 30 minutes after administration.

The EEjjQ value for the test compound is the dose which, for <* causes loss of the erection reflex in $ 50 of the mice in a group that 1 absence of oral therapy would not be expected to lose the erection reflex. The results are shown in Table 3 below.

7) Experiments on rotating drum (mice) (RDM).

In groups of 10 mice, oral vehicle plus test compound is injected at different dose levels, with a control group receiving vehicle alone. 30 minutes after administration, each group of mice is placed on a 30 cm diameter rotating drum which rotates at one revolution per minute. The mice are placed on the drum against their direction of movement and the number of mice dropping off in 2 minutes is noted. Hd from the results obtained, a 27 U1250 dose response curve is constructed and the dose »which causes 50 $ of the mice to fall off the drum (ED ^ 0) is estimated. The results are shown in Table 5 below.

8) Acute toxicity in mice (ATM).

Experiments are performed to determine acute toxicity by oral and intraperitoneal administration using groups of 10 mice at different dose levels. The mortality of the groups is found after 24 hours and the results in mg / kg are shown in Table 5 below.

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141250 29

The results obtained show that the compounds prepared according to the invention have a very significant effect on the central nervous system such as anti-convulsion, anti-anguish and hypnotic sedatives and that they have a very low toxicity.

Claims (2)

141250 30 Patent Claims. Analogous Process for the Preparation of 1,2-Dihydro-6-phenyl-1H, 4H-imidazole, 2-a7i / r, 7benzodiazepine-1-ones of the general formula Ic h Λ x \ (Wi V Rl ^ ^ represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, 2 R, which may be in any suitable position on the phenyl ring, represents a hydrogen atom or a halogen atom and wherein A ς either R and R, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, a hydroxyalkyl group having 1-5 carbon atoms, an aminoalkyl or alkylaminoalkyl group (each of which the alkyl moieties each contain 1-5 carbon atoms), a phenyl or naphthyl group or a cycloalkyl group having 3-8 carbon atoms, 45 or R with the nitrogen atom represents pyrrolidinyl, piperidino, morpholino, thiomorpholino or piperazin-1-yl, optionally substituted with methyl, R-hydroxyethyl, R-phenyl, 4- (1,1-phenyl-5'-imidazolyl-4'-one ), allyl, R-cyclopropylmethyl or R-dimethylphosphinylmethyl, or acid addition salts thereof, characterized in that a compound of the formula V / VL · / 0 ~ R * 1 2 wherein R and R have the same meaning as above is reacted with a dimethylformamide acetal of formula TI (AlK-O) 2 = CH - 5 = (CH wherein A1K represents an alkyl group having 1 to 5 earbone atoms to form 8-R1, 1,2-dihydro-2- (dimethylamino) methylene-6- (R2-phenyl) -IH, 4H- imidazo / 1,2-a7 / T, 47benzodiazepine-1-one of the formula la «vA * I> fύηΛ Wherein Rx and R have the same meaning as above, and that optionally the compound of formula Ia is either converted to salt or transaminated by reaction with an appropriate amine of formula VIII Η - N - R 4 • ς (VIII) R R 1 has the same meaning as above with the exception that